Initiation Of Systemic Therapy Research Articles

Abstract PO4-15-01: A multi-center prospective cohort study to evaluate the presence of circulating tumor cells using the Epic Sciences platform among women with metastatic breast cancer

Abstract Background: The presence of tumor cells (or their components) in the blood of women with a history of early breast cancer has the potential to herald the development of metastatic recurrence at its earliest stages. Such early detection could potentially lead to novel prevention strategies, but it requires a sensitive assay. Objective: To use the Epic Sciences platform to detect and enumerate CTCs in blood samples from patients with an established diagnosis of metastatic breast cancer (MBC), prior to initiation of 1st line systemic therapy in the metastatic setting. Methods: We conducted a multi-center prospective cohort study to evaluate the presence of CTCs using the Epic Sciences platform among patients with a new diagnosis of MBC. Men or women age 18 to 85 were included, irrespective of breast cancer subtype. Patients with a prior or concurrent malignancy whose natural history or treatment had the potential to interfere with the detection of MBC in a liquid biopsy were excluded. A one-time blood draw was performed before patients received any local or systemic therapy in the metastatic setting. In addition, those with recurrent disease must have been off any systemic adjuvant therapy for ≥3 weeks prior to blood collection. Two 5 mL blood samples were obtained for CTC identification and enumeration. CTC identification was based on immunofluorescence analysis using Epic Sciences platform as previously described (Ueno et al 2017). The presence of CTCs was correlated with clinical and pathological features, which were abstracted from medical records and pathology reports. The association between the presence of CTCs and clinical/pathologic characteristics was tested using Fisher’s exact test for categorical variables and t-test or Wilcoxon rank sum tests for numerical variables. All analyses were performed using the R software package. Results: 100 patients were recruited between February 2021 and January 2023 at five academic oncology centres in Ontario and Quebec, Canada. 95 patients had evaluable blood for analysis and 5 did not due to blood age and/or insufficient blood volume. Six patients were excluded after providing a blood sample because tissue biopsy ultimately revealed a 2nd primary tumor (n=4) or benign tissue (n=2). Hence, 89 patients with a clinical diagnosis of MBC and with evaluable blood for CTC analyses were ultimately included in our cohort. The average age of patients was 61 years. Most patients (n=49, 55%) had a prior history of early breast cancer, 38 (43%) had de-novo metastatic disease and prior breast cancer history was unknown for 2 patients. 50 (66%) of patients had visceral metastatic disease. The most common sites of metastases included bone (62%), lung (30%), liver (29%) and lymph nodes (17%). 63 of 89 patients (71%) had detectable CTCs at baseline, prior to any local or systemic treatment in the metastatic setting. The median number of detectable CTCs per 5mL sample was 2 (IQR 8.5) and the range was 0 – 12,798. Twenty nine of 89 (33%) patients had 5 or more CTCs detected per 5ml blood. The proportion of patients with detectable CTCs was numerically highest (n=39/51, 76%) among patients with hormone receptor (HR)+/HER2-ve breast cancer, followed by HER2+ (n=16/22, 73%) and triple negative (n=8/13, 62%) disease. Associations between CTC detection with prior history of early breast cancer, sites of metastatic disease and disease burden will also be presented. Conclusions: Approximately 3 in 4 women with newly diagnosed metastatic breast cancer have detectable CTCs using the Epic Sciences platform prior to initiation of first line systemic therapy. CTCs may be a promising tool for the monitoring of breast cancer recurrence and will be investigated in an ongoing Canadian prospective observational study that aims to elucidate biomarkers of late breast cancer recurrence. Citation Format: Katarzyna Jerzak, Pamela Goodwin, Marguerite Ennis, Christine Brezden-Masley, Nathaniel Bouganim, Mark Basik, Arushi Jain, Giuseppe Di Caro, Rick Wenstrup, Nadine Hartmann, Megan Slade, Ana Elisa Lohmann. A multi-center prospective cohort study to evaluate the presence of circulating tumor cells using the Epic Sciences platform among women with metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-15-01.

Abstract PS04-01: Clinical impact of timing of systemic therapy in patients with early triple negative breast cancer

Abstract Introduction TNBC is known for its aggressive nature, with early recurrence and limited treatment options beyond chemotherapy and recently immunotherapy. We aim to clarify, whether timing of systemic therapy has an impact on survival in patients with early TNBC. Methods Data from a large population-based regional cancer registry covering over 2.2 million people was used for evaluation, including women with diagnoses of TNBC between 2010 and 2018. Patients were categorized into subgroups according to the interval from TNBC pathologic diagnosis to the date of first administration of NACT (TTNC) or according to the interval from primary surgery to the date of first administration of adjuvant chemotherapy (TTAC). Univariable analyses of survival rates were conducted using the Kaplan-Meier method, the log-rank test was used for group comparisons. IBM SPSS Statistic 25 was used to perform statistical analysis, with hazard ratios, p-values, and 95% confidence intervals calculated for each model. All tests were two-sided, and significance was set at p < .05. Results We identified 37 382 patients with malignant neoplasms of the mammary gland. The final study cohort included 732 patients with early TNBC, of whom 43.6% were treated with NACT and 40.3% with adjuvant chemotherapy. Timing of NACT 270 patients with TNBC treated with NACT had a valid TTNC. Median follow up was 3.5 years. Patients with TTNC ≤14, ≤42, >42, and >56 days had estimated mean OS of 8.4, 6.9, 4.6, and 3.3 years, respectively. Patients with a TTNC ≤14 days were more likely to survive than patients with a TTNC ≥ 56 days (p= 0.054). Significance was barely not reached in the group of NACT. Timing of adjuvant chemotherapy 245 patients with TNBC treated with adjuvant chemotherapy had a valid TTAC. Treatment given within 22-28 days led to the best outcome with a mean OS of 10.2 years, while later treatment (29-35, 36-42 days, or >6 weeks) had significant reduced mean OS of 8.3, 7.8, and 6.9 years. Patients who received therapy within 22-28 days had significantly better survival than those who received therapy between 29-35 days (p=0.043) or after more than 43 days (p=0.033). Conclusion Although significance was barely not reached in the subgroup of patients treated with NACT, the results in this large population-based study indicate that there are critical time intervals for initiation of systemic therapy in patients with early TNBC, with reduced OS if NACT is applied later than 42 days after diagnosis or if adjuvant chemotherapy is applied later than 42 days after surgery. We recommend not to exceed the 6-week interval until the initiation of systemic therapy in patients with early TNBC. Citation Format: Maria Eleni Hatzipanagiotou, Miriam Pigerl, Michael Gerken, Sophie Räpple, Verena Zeltner, Madeleine Hetterich, Elisabeth C. Inwald, Monika Klinkhammer-Schalke, Olaf Ortmann, Stephan Seitz. Clinical impact of timing of systemic therapy in patients with early triple negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS04-01.

Abstract PO5-18-04: Effect of Digoxin on clusters of circulating tumor cells in patients with metastatic breast cancer (DICCT)

Abstract Background: The presence of circulating tumor cell (CTC) clusters is associated with tumor progression and with a bad prognosis in various cancer types1,2. In breast cancer, a pre-clinical model demonstrated that Na/K-ATPase inhibitors such as digoxin could dissolve CTC clusters and reduce metastasis3. DICCT is a single-arm, therapeutic exploratory phase I study aimed to examine whether digoxin can disrupt CTC clusters in metastatic breast cancer patients (NCT03928210). Material and methods: Metastatic breast cancer patients in whom clusters of CTCs have been detected were eligible. Patients with concomitant heart disease were excluded. After progressive disease in any line of therapy, a window of opportunity before initiation of subsequent systemic therapy was used to administer digoxin treatment for seven (7) days. For CTC detection, blood samples were processed with the FDA-cleared Parsortix system (ANGLE plc, UK). Captured CTCs were stained for EPCAM, HER2, EGFR (positive CTC selection) and CD45 (exclusion marker). To gain insight into the cluster-dissolution ability of digoxin, the primary endpoint was size of CTC clusters (i.e. number of cells within each cluster) under digoxin therapy. The cumulative effect of digoxin treatment on the primary endpoint was assessed by a linear regression model. Results: Nine (9) patients with CTC clusters detected at baseline were enrolled. A target level of digoxin above 0.7 ng/ml could be confirmed at day 7 for all patients. For quantitative and qualitative analysis of CTC clusters, 5.5 to 27 ml of blood were analyzed at baseline, at day 0 pre-treatment, and post 2 hours, 3 days and 7 days of digoxin treatment. The average cluster size ranged between 2 and 11.8 cells (median 2.9) considering all samples from all patients. Digoxin treatment reduced cluster size in 8 patients (88.9%) to different extents, and the proportion of CTC cluster over single CTCs was also reduced in 6 patients (66.7%). The effect of digoxin was evident in both homotypic (cancer cells only) and heterotypic (aggregates of CTCs and white blood cells) clusters. The treatment was well tolerated, and no adverse events related to the study treatment occurred. All patients completed the treatment according to the protocol. Conclusion: DICCT provides the first-in-human proof-of-principle that digoxin induces a partial dissolution of CTC clusters in patients with metastatic breast cancer at drug levels that are safe and well tolerated. Conceptualization of follow-up trials including Na/K-ATPase inhibitors and patient outcome endpoints are underway.

Racial disparities in the attainment of textbook oncologic outcomes following colectomy for colon cancer: a national cancer database cohort study.

Textbook oncologic outcome (TOO) is attained when all desired short-term quality metrics are met following an oncologic operation. The objective of this study was to determine the impact of race on TOO attainment following colectomy for colon cancer. The 2004-2017 National Cancer Database was queried for patients with non-metastatic colon cancer who underwent colectomy. TOO was defined as: negative margins (R0), adequate lymphadenectomy (LAD) (n ≥ 12), no prolonged length of stay (LOS), no 30-day readmission or mortality, and initiation of systemic therapy in ≤ 12weeks. Racial groups were defined as White, Black, or Hispanic. 508,312 patients were identified of which 34% achieved TOO. Blacks attained the least TOO (31.4%) as well as the TOO criteria of adequate LAD (81.1%), no prolonged LOS (52.3%), and no 30-day readmission (89.7%). Hispanics were least likely to have met the criteria of R0 resection (94.3%), no 30-day mortality (87.3%), and initiation of systemic therapy in ≤ 12weeks (81.8%). Patients who attained TOO had a higher median overall survival (OS) than those without TOO (148.2 vs. 84.2months; P < 0.001). Hispanic TOO patients had the highest median OS (181.2months), while White non-TOO patients experienced the lowest (80.2months, P < 0.001). Multivariate logistic regression models suggest that Black and Hispanic patients are less likely to achieve TOO than their White counterparts. Racial disparities exist in the achievement of TOO, with Blacks and Hispanics being less likely to attain TOO compared to their White counterparts.

A Combined Cyto- and Histopathological Diagnostic Approach Reduces Time to Diagnosis and Time to Therapy in First Manifestation of Metastatic Spinal Disease: A Cohort Study.

Malignant spinal lesions (MSLs) are frequently the first manifestation of malignant disease. Spinal care, diagnostic evaluation, and the initiation of systemic therapy are crucial for outcomes in patients (pts) with advanced cancer. However, histopathology (HP) may be time consuming. The additional evaluation of spinal lesions using cytopathology (CP) has the potential to reduce the time to diagnosis (TTD) and time to therapy (TTT). CP and HP specimens from spinal lesions were evaluated in parallel in 61 pts (CP/HP group). Furthermore, 139 pts in whom only HP was performed were analyzed (HP group). We analyzed the TTD of CP and HP within the CP/HP group. Furthermore, we compared the TTD and TTT between the groups. The mean TTD in CP was 1.7 ± 1.7 days (d) and 8.4 ± 3.6 d in HP (p < 0.001). In 13 pts in the CP/HP group (24.1%), specific therapy was initiated based on the CP findings in combination with imaging and biomarker results before completion of HP. The mean TTT in the CP/HP group was 21.0 ± 15.8 d and was significantly shorter compared to the HP group (28.6 ± 23.3 d) (p = 0.034). Concurrent CP for MSLs significantly reduces the TTD and TTT. As a result, incorporating concurrent CP for analyzing spinal lesions suspected of malignancy might have the potential to enhance pts' quality of life and prognosis in advanced cancer. Therefore, we recommend implementing CP as a standard procedure for the evaluation of MSLs.

Longitudinal treatment outcomes of recurrent clival chordomas: a single-center retrospective study.

The objective of this study was to clarify the detailed clinical course of recurrent clival chordoma and the outcomes of each treatment modality. A single-center retrospective analysis was conducted on patients seen for recurrent clival chordoma. The cohort was identified from those who underwent surgery, stereotactic radiosurgery, or proton therapy at the authors' institution between 1990 and 2022. A total of 95 recurrences in 40 patients with a median (interquartile range [IQR]) follow-up of 43 (18-79) months were identified. The median (IQR) age at the time of diagnosis was 48 (36-62) years, and 55% of patients were male. Twenty-three patients were treated with surgery followed by adjuvant radiation before the first recurrence. The median (range) number of recurrences per patient was 2 (1-8), and the median (IQR) time to the first recurrence was 29 (9-51) months. The recurrences were treated with one or more of the following therapies: surgery, radiation, systemic therapy, and laser interstitial thermal therapy (LITT). Surgery was performed for 44 recurrences in 25 patients. Radiation was used to treat 42 recurrences in 28 patients. Patients with recurrences treated with surgery plus radiation had the longest progression-free survival (PFS) (median [95% CI] overall survival [OS] 120 [0-245] months, p < 0.01, log-rank test). Patients with recurrences but without prior radiation had longer PFS than those patients with prior radiation. The median (95% CI) OS after the first recurrence was 68 (54-82) months, 5-year OS after the first recurrence was 48%, and 10-year OS was 27%. Multivariate Cox regression analysis showed that mortality after the first recurrence was significantly associated with no adjuvant radiation (HR 0.149, 95% CI 0.038-0.59, p = 0.0067), older age at the time of the first recurrence (HR 1.04, 95% CI 1.01-1.08, p = 0.021), and total number of recurrences (p = 0.032). Seven patients received systemic therapy, and the median (95% CI) OS of these patients since initiation of systemic therapy was 31 (11-51) months. Imatinib and/or nivolumab were used in 6 patients (15%). One patient (3%) was treated with LITT for his fourth recurrence. Despite the aggressive nature of recurrent chordoma, 14 of 29 patients (48%) survived for more than 5 years after the initial recurrence using combined therapies. Multiple treatment options may contribute to the long-term survival of patients with this intractable tumor.

Prediction of cognitive decline in older breast cancer survivors: the Thinking and Living with Cancer study.

Cancer survivors commonly report cognitive declines after cancer therapy. Due to the complex etiology of cancer-related cognitive decline (CRCD), predicting who will be at risk of CRCD remains a clinical challenge. We developed a model to predict breast cancer survivors who would experience CRCD after systematic treatment. We used the Thinking and Living with Cancer study, a large ongoing multisite prospective study of older breast cancer survivors with complete assessments pre-systemic therapy, 12 months and 24 months after initiation of systemic therapy. Cognition was measured using neuropsychological testing of attention, processing speed, and executive function (APE). CRCD was defined as a 0.25 SD (of observed changes from baseline to 12 months in matched controls) decline or greater in APE score from baseline to 12 months (transient) or persistent as a decline 0.25 SD or greater sustained to 24 months. We used machine learning approaches to predict CRCD using baseline demographics, tumor characteristics and treatment, genotypes, comorbidity, and self-reported physical, psychosocial, and cognitive function. Thirty-two percent of survivors had transient cognitive decline, and 41% of these women experienced persistent decline. Prediction of CRCD was good: yielding an area under the curve of 0.75 and 0.79 for transient and persistent decline, respectively. Variables most informative in predicting CRCD included apolipoprotein E4 positivity, tumor HER2 positivity, obesity, cardiovascular comorbidities, more prescription medications, and higher baseline APE score. Our proof-of-concept tool demonstrates our prediction models are potentially useful to predict risk of CRCD. Future research is needed to validate this approach for predicting CRCD in routine practice settings.

Treatment-free survival outcomes from the phase II study of nivolumab and salvage nivolumab/ipilimumab in advanced clear cell renal cell carcinoma (HCRN GU16-260-Cohort A)

BackgroundAs part of a partitioned survival analysis, treatment-free survival (TFS) can characterize the overall survival time patients spend between the cessation of immunotherapy and the start of subsequent therapy; both...

Abstract 2526: Exploratory study of predicting systemic therapy response by IGRA in advanced stage NSCLC patients

Abstract Purpose: In this study, we aim to prospectively evaluate how patients’ pretreatment PSIG correlated with chemotherapy, immune checkpoint inhibitors (ICI) and epidermal growth factor receptor (EGFR) Tyrosine Kinasae Inhibior (TKI). Also, to assess the change of PSIG during anti-cancer treatment and the relation with clinical condition. Materials and Methods: Newly diagnosed advanced stage non-small cell lung cancer patients were enrolled. The inclusion criteria included pathology or cytology-proved stage IV and non-operable stage III non-small cell lung cancer, treatment-naïve, and planned to receive chemotherapy, EGFR-TKI therapy. Or, planned to receive any line of singe agent immunotherapy. We planned to enroll 30 patients in each treatment group (chemotherapy, immunotherapy, EGFR TKI therapy) with and additional control group of stage I NSCLC.Blood sample from each enrolled patient was obtained for INF-γ release assay (IGRA) within 3 days before the initiation of systemic therapy and 8-12 weeks after treatment. The IGRA was performed with QuantiFERON-TB In-Tube (QFT-GIT; Qiagen, Germany) according to the manufacture’s instruction. The amount of INF-γ produced in response to PHA is determined by the INF-γ level in the PHA-coated tube minus saline-coated tube, and is termed PHA-stimulated INF-γ (PSIG) level. Patients with PSIG level above 7.06IU were defined had high PSIG level according to our previous study. we also performed our in house INF-γ level by ELISA. Tumor response was assessed mainly by chest CT and brain MRI (if available) according to Response Evaluation Criteria in Solid Tumors (RECST). Results: Total 116 patients were enrolled. Demographic distribution was summarized in Table 1. Thirty-five of 116 (30.2%) patients had latent TB infection, while 12 patients (10.3%) had indeterminate OFT test, all due to low mitogen-stimulated INF-γ level. 84 patients had been obtained post-treatment blood test, and the box-plot of in-house INF-γ level were shown in Figure1. For stage I control group, INF-γ level seemed higher after surgery; for chemotherapy and immunotherapy, the INF-γ level also seemed increase among responders (who achieved disease control after treatment). There were no statistically difference of disease control rate between patients with high PSIG level and low PSIG level. Overall survival also showed no statistically difference between 2 PSIV level patient group among advanced stage NSCLC patients. Conclusions:There were no statistically different of disease control rate in PSIG high and low group. The increased trend of INF-γ level after surgery, immunotherapy and chemotherapy may suggested improving immune function after treatment even in the very early disease stage. Citation Format: Hsu Ching Huang, Chi-Lu Chiang, Yung-Hung Luo, Yuh-Min Chen, Chao-Hua Chiu. Exploratory study of predicting systemic therapy response by IGRA in advanced stage NSCLC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2526.

A Pooled Analysis of Treatment-Free Survival in Advanced Renal Cell Carcinoma.

A clinically meaningful attribute of some immune-oncology (IO) regimens is potential durable clinical benefit during a treatment-free interval. We characterize treatment-free survival (TFS) with and without ongoing toxicity in trials of frontline IO-VEGF tyrosine kinase inhibitor (TKI) combinations in patients with advanced renal cell carcinoma (aRCC). Individual patient data were pooled by treatment arm from randomized trials submitted to the FDA evaluating IO-TKI combination in treatment-naïve aRCC with at least 30 months of median follow-up. OS, TFS, TFS with and without toxicity, and time to all protocol therapy cessation were assessed. TFS was estimated by 30-month restricted mean times defined as area between Kaplan-Meier curves for two time-to-event endpoints originating at randomization: time to all protocol therapy cessation and time to subsequent systemic therapy initiation or death. Three trials met criteria for analysis; 1183 pts received IO-TKI versus 1184 on control arms received TKI alone (sunitinib [SUN]). IO-TKI and SUN groups spent 9% (2.7 months [95% confidence interval (CI): 1.8, 3.5]) and 10% (2.9 months [95% CI: 2.1, 3.8]) of the 30-mo period alive and treatment-free, respectively. Mean TFS without grade ≥3 toxicity was 1.7 and 2.3 months in IO-TKI and SUN groups, respectively. In this post hoc partitioned survival analysis, TFS and TFS without toxicity appeared similar in the IO-TKI group compared to the SUN group. These findings may reflect continuation of TKI until progression per protocol design in all trials and discontinuation of IO after 2 years in 2 trials.

Genomic amplifications identified by circulating tumor DNA analysis guide prognosis in metastatic castration-resistant prostate cancer.

Analysis of circulating tumor DNA (ctDNA) in patients with metastatic prostate cancer (mPC) provides an opportunity to identify and monitor genomic alterations during a patient's treatment course. We evaluated whether the presence of specific gene amplifications (GAs) and plasma copy number (PCN) alterations are associated with disease features. This is a single-institution retrospective study of patients with mPC who underwent ctDNA profiling using Guardant360® (Guardant Health Inc.). This test identifies single nucleotide variants (SNVs) and GAs of select genes by next-generation sequencing. A total of 155 men with mPC were studied. Patients were stratified by GA status. The Kaplan-Meier method and multivariate cox regression models were used to estimate overall survival (OS) or failure-free survival (FFS) from either the date of GA detection or the initiation of systemic therapy. The chi-square test was used to evaluate associations between clinical factors and GAs. The presence of liver and/or lung metastases was associated with GAs of BRAF, CDK6, PI3KCA, and FGFR1. Survival analyses were completed on a subset of 83 patients with metastatic castration-resistant prostate cancer (mCRPC). Median OS was improved in patients with 1 GA compared to patients with ≥2 GAs, whether determined from the date of initial GA(s) detection (14.9 mo vs. 8.9 mo) or date of therapy initiation nearest to GA detection (16.7 mo vs. 9.0 mo). Patients without GAs had not reached median OS. Patients with androgen receptor (AR) GA only were also found to have better median OS compared to patients with AR GA plus at least one other additional GA (19.3 mo vs. 8.9 mo). Patients with PIK3CA GA had significantly lower median OS compared to patients with GAs that did not have a PIK3CA GA (5.9 mo vs. 16.0 mo). In patients with AR and/or MYC GA(s), median OS improved in those with reduced AR or MYC PCN during therapy compared to those without such a reduction (25.1 mo vs. 15.9 mo). The association of select GAs with survival provides an additional tool for assessing mCRPC prognosis and informing management. Serial monitoring of ctDNA GAs is also useful to guide prognosis and therapeutic response.

569 - Impact of therapeutic inertia on patient-reported outcomes in moderate-to-severe atopic dermatitis: a 12-month longitudinal study from the TARGET-DERM AD registry

Abstract Background Therapeutic inertia, defined as the delay or reluctance in modifying treatment when goals are unmet, is a significant challenge in managing chronic diseases, including atopic dermatitis (AD). This inertia can lead to suboptimal control of the disease, affecting patient outcomes. Objectives This study aims to evaluate the effect of therapeutic inertia on patient-reported outcomes (PROs) in individuals with moderate-to-severe AD undergoing systemic treatment over 3 to 12 months. Methods We analyzed longitudinal data from the TARGET-DERM AD registry, which includes 3,457 patients with moderate-to-severe AD from 39 centers across the U.S. and Canada. Eligible patients had documented outcomes at the initiation of systemic therapy and at subsequent 3-month intervals up to 12 months of follow-up. We assessed patient-reported outcomes (PROs) to determine the proportion of patients not meeting predefined treatment targets for PROs based on expert consensus. Patients had a validated Investigator Global Assessment (vIGA-AD) score of 3 or more at initiation of either an advanced systemic therapy (AST) such as biologics or JAK inhibitors or a conventional systemic therapy (CST) such as cyclosporine, methotrexate, or prednisone. PROs were evaluated at 3-month intervals up to 12 months, assessing achievement against predefined treatment targets based on expert consensus. PRO measures included Worst-Itch (PROMIS Itch-Severity), POEM, PO-SCORAD, NRS-sleep, and NRS-pain with specific moderate and optimal target levels established for each. Itch-Severity (range: 0–10; moderate target: ≥4-point reduction, optimal target: score ≤1), POEM (range: 0-28; moderate target: ≥4-point reduction, optimal target: score ≤2), PO-SCORAD (range: 0-103; moderate target: score ≤24; optimal target: score ≤10), NRS-sleep and NRS-pain (range: 0-10; moderate target: reduction ≥3-points; optimal target: score ≤1). Results Out of 2107 patients with moderate-to-severe AD, 445 qualifying participants were included (63.8% adult, 62.0% female, 45.4% Non-Hispanic White, mean age of 31 years). Most patients (88.8%) initiated AST, with dupilumab being the most common (86.5%). At 6 months, significant proportions of AST-treated patients failed to reach moderate and optimal targets for itch (67% and 79%, respectively), POEM (46% and 69%), and NRS-sleep (59% and 47%). By 12 months, these figures were similar, with 66% and 88% failing to meet itch targets, 53% and 73% failing to meet POEM targets, and 62% and 45% failing to meet NRS-sleep targets, respectively. A similar pattern was observed for other PROs. CST-treated patients exhibited similar trends. Conclusions The study highlights the profound impact of therapeutic inertia on the quality of life of patients with moderate-to-severe AD. Despite systemic therapy, a considerable proportion failed to meet treatment targets over a 12-month period, underscoring the need for more proactive and responsive treatment strategies in AD management.

568 - Persistent inadequate disease control and therapeutic inertia in moderate-to-severe atopic dermatitis: a 12-month longitudinal analysis of real-world outcomes from TARGET-DERM registry

Abstract Background Therapeutic inertia refers to the delay or failure to escalate treatment in patients who are not achieving adequate disease control and poses a challenge in the management of moderate-to-severe atopic dermatitis (AD). Despite the availability of conventional (CST) and advanced systemic therapies (AST) currently utilized for the treatment of moderate to severe AD, many patients do not achieve treatment success. However, the extent of this inadequacy in real-world clinical practice remains underexplored. Objectives This study aims to evaluate the occurrence therapeutic inertia (assessed as non-escalation of therapy despite limited disease control) and the proportion of patients with moderate-to-severe AD who continue to show an inadequate response after receiving systemic therapies for a duration ranging from 3 to 12 months. Methods We conducted a longitudinal analysis of patients with moderate-to-severe AD (vIGA-AD≥3) from the TARGET-DERM AD registry, including 3,457 participants from 39 centers in the U.S. and Canada. Eligible patients had documented outcomes at the initiation of systemic therapy and after 3 months up to 12 months of follow up. We assessed clinician- and patient-reported outcomes to identify the proportion of patients not meeting pre-defined targets based on expert consensus. An inadequate response was defined as not achieving a validated Investigator Global Assessment (vIGA-AD) score ≤2, a 50% improvement in Body Surface Area (BSA), and a ≥4-point reduction in the Worst Pruritus Numeric Rating Scale (WP-NRS). An optimal response was defined as a vIGA-AD score ≤1 (clear or almost clear skin), BSA ≤2%, and WP-NRS itch score of 0/1 (complete or almost complete skin resolution). Results Out of 2,107 patients with moderate-to-severe AD, 445 met the inclusion criteria. The majority were adults (63.8%), female (62.0%), and Non-Hispanic White (45.4%), with an average age of 31 years. Most patients (88.8%) initiated treatment with AST, with dupilumab being the most common (86.5%). The mean vIGA-AD was 3.3 for AST and 3.6 for CST at initiation (P&amp;lt;0.01). At 6 months, 37% and 67% of AST-treated patients had inadequate responses in terms of skin clearance and itch outcomes, respectively, while 82% and 79% did not achieve optimal responses. At 12 months, these figures were approximately 30% and 66% for inadequate responses and 85% and 88% for not achieving optimal responses, respectively. CST-treated patients showed a similar trend. Conclusions The study reveals a significant portion of moderate-to-severe AD patients fail to achieve adequate disease control with systemic therapies over 12 months, indicating a substantial presence of therapeutic inertia. These findings suggest a need for more proactive management strategies in AD treatment.

Overall survival with darolutamide vs placebo in combination with androgen-deprivation therapy (ADT) and docetaxel: A sensitivity analysis from ARASENS accounting for subsequent therapy.

166 Background: Darolutamide (DARO) + ADT + docetaxel (DOC) is approved for metastatic hormone-sensitive prostate cancer (mHSPC) based on the phase 3 ARASENS study (NCT02799602). To address the impact of informative intercurrent events (eg, use of subsequent therapy) in censored patients (pts), as defined by the European Medicines Agency, we performed a post hoc sensitivity analysis of OS. Methods: Pts with mHSPC were randomized 1:1 to oral DARO 600 mg twice daily or placebo (PBO) + ADT + DOC. The primary endpoint was OS using a log-rank test, with HR (95% CI) calculated by Cox model, stratified by extent of disease (EoD; nonregional lymph node vs bone ± lymph node vs visceral ± lymph node/bone metastases) and alkaline phosphatase (&lt; vs ≥ upper limit of normal). Pts with no documented death were censored at last known alive or data cut-off date, whichever was earlier. The post hoc sensitivity analysis counted initiation of subsequent systemic antineoplastic therapy as an event in censored pts still alive at end of follow-up. In addition planned sensitivity analyses used an unstratified log-rank test/Cox model, a log-rank test/Cox model with stratification factors from electronic case report forms, and a log-rank test/Cox model with EoD stratification factors from central imaging review. Results: In the primary analysis DARO + ADT + DOC significantly improved OS ( P&lt;0.0001; Table), despite a high percentage of pts who entered follow-up in the PBO group receiving subsequent life-prolonging systemic therapies (374/495, 76%). Time to first subsequent systemic antineoplastic therapy (a key secondary endpoint) was significantly longer with DARO + ADT + DOC vs PBO + ADT + DOC (HR 0.39, 95% CI 0.33–0.46, P&lt;0.001). Findings from the post hoc sensitivity analysis counting initiation of subsequent systemic antineoplastic therapy as an event in censored pts (pts with events: DARO 300/651, 46.1%; PBO 476/654, 72.8%) and the planned sensitivity analyses were consistent and supported the primary OS analysis (Table). Treatment-emergent adverse events (TEAEs) were similar between groups. TEAEs led to DARO/PBO discontinuation in 13.5%/10.6% of pts. Conclusions: The results of the post hoc and planned sensitivity analyses were consistent with and supportive of the ARASENS primary OS analysis. These data reinforce DARO + ADT + DOC as an effective and well tolerated new standard of care for early treatment intensification in pts with mHSPC. Clinical trial information: NCT02799602 . [Table: see text]

Upfront Multiplex Gene Test Helps Prolong Survival in Advanced Non-small Cell Lung Cancer.

Detection of genetic abnormalities is crucial for selecting an appropriate therapy to effectively treat advanced non-small cell lung cancer (NSCLC). Multiplex genetic testing aids the selection of appropriate therapy and tailored treatments; however, its impact on survival remains unexplored. Using data from 112 patients with advanced or recurrent NSCLC between February 2020 and April 2023, we investigated the impact of multiplex genetic tests, conducted before the initiation of systemic therapy, on survival. Multiplex genetic test was performed on 72 patients (MPL group). Among the remaining 40 patients (non-MPL group), 18 underwent ≥1 single-plex genetic test, including tests for EGFR (18), ALK (14), and ROS1 (8). The frequency of EGFR mutations in the MPL and non-MPL groups was similar (28% and 25%, respectively), whereas alterations in KRAS, ALK, MET, HER2, and RET levels (5, 4, 4, 4, and 1, respectively) were exclusively detected in the MPL group. The MPL group exhibited a significantly improved survival rate compared to the non-MPL group (median survival time 20.6 vs. 9.3 months, p=0.009). Multiplex genetic testing, before the initiation of systemic treatment, could potentially enhance prognosis by uncovering a wide range of non-EGFR gene abnormalities. Multiplex genetic tests could be crucial for the effective application of modern anticancer therapeutic strategies.

Systemic and surgical treatment in renal cell carcinoma: Does timing matter?

417 Background: Today, targeted systemic therapy is standard 1st line treatment of advanced/metastatic renal cell carcinoma (aRCC). Upfront cytoreductive nephrectomy (CN) has been an important treatment option. Recently its role is under debate, especially in combination with the new 1st line treatments. Our study evaluated the current relevance of initial surgical intervention and the role of inductive systemic therapy in aRCC. Methods: We included 33 patients with aRCC from the University Hospitals in Essen and Münster initiating 1st line treatment from 03/18 to 01/23 pre or post surgery. We retrospectively formed two cohorts, either CN followed by systemic therapy (cohort 1; 13 patients) or vice versa (cohort 2; 20 patients). Patients received either Ipilimumab/Nivolumab (Ipi/Nivo) (42.4%) or a checkpoint inhibitor and tyrosine kinase inhibitor (CPI/TKI) combination (57.6%). Progression-free survival (PFS) was estimated with Kaplan-Meier-method from initiation of systemic therapy or CN to progression or death. In Cohort 2, we additionally analyzed the radiologic response of the primary measured by change of the longest diameter. The radiographic response was analysed according to RECIST1.1. Results: Patients’ age ranged from 44 to 80 years with a median of 63 years. Intermediate and poor prognosis occurred in 61.3% and 38.7% of cases. The two cohorts did not differ significantly regarding baseline characteristics. Median PFS was 8 vs. 23 months (p=0.03) in cohort 1 (95% CI 0.9-15.1) compared to cohort 2 (95% CI 18.8-27.2). In cohort 2 the time between start of systemic therapy and surgery was in median 8.5 months (95% CI 3.3-21.1), the primary had a median diameter of 10.7 cm (95% CI 4.5-13.3). Median reduction of the primary was in total 32.2%, 28.9% in the Ipi/Nivo and 34.7% in the CPI/TKI group (p=0.74). In seven patients (35%) response led to modification of the surgical approach, enabling partial instead of radical nephrectomy. Conclusions: The sequence of systemic therapy followed by surgery was associated with a significant PFS benefit. In addition, prior systemic therapy led to a primary reduction and better operability, in some cases even to kidney sparing surgery. Major limitation is the retrospective nature of our analysis and a potential selection bias. However, the sequence of prior systemic therapy followed by surgery in aRCC was associated with notably better outcomes.

Time to next systemic therapy after stereotactic body radiation therapy for oligoprogressive metastatic castrate-resistant prostate cancer.

62 Background: Patients with castrate-resistant prostate cancer (CRPC) with progressive disease are generally require a change/escalation in systemic therapy. For patients with limited ( ≤3) sites of progressive disease (oligoprogression), metastasis-directed therapy with stereotactic body radiation therapy (SBRT) may allow a longer interval before next line systemic therapy, but there is limited data describing this approach. Methods: This is a retrospective study of patients with oligoprogressive metastatic CRPC (omCRPC) treated with SBRT at a single center between 2011-2022. The primary endpoint was time to next systemic therapy (TTNST) after SBRT. Secondary endpoints included overall survival (OS) after SBRT and TTNST stratified by presence of untreated non-progressing metastases. Results: Thirty-two patients with omCRPC received SBRT to 38 metastases. Patients had a median age of 72.5 years (range 50.6-84.3) and median PSA 6.85 ng/mL (range 0.39-922.0) at time of SBRT. The majority had an ECOG of 1-2 (29 patients, 90.6%) and metastases detected on conventional CT and/or bone scans (26 patients, 81.3%). The most commonly utilized SBRT regimen was 3000 cGy in 5 fractions (18 metastases, 47.4%) (Table). Sixteen patients were treated to all known sites of disease, whereas 16 patients received SBRT to oligoprogressive metastases but had at least one untreated non-progressing metastasis at the time of SBRT. Of 32 patients, 23 (65.7%) received SBRT to bone only, 3 (9.4%) to lymph node (LN) only, and 6 (18.8%) to other sites (pelvic tumor, n=2; pelvic tumor + LN, n =1; LN + bone, n=1; dura + bone, n=1; liver, n=1). Patients had received a median of 1.0 prior line of androgen receptor signaling inhibitors and were predominantly (26 patients, 81.3%) chemotherapy naïve. Following SBRT, the median TTNST was 10.1 months and median OS was 41.3 months. For patients with 0 versus ≥1 untreated non-progressing metastasis, TTNST was 11.3 versus 8.7 months, respectively (HR 0.67, 95% CI 0.33-1.36, logrank p=0.24). There were no grade ≥3 toxicities due to SBRT. Conclusions: In this cohort, patients with omCRPC treated with SBRT delayed the next line of systemic therapy for a median of 10.1 months. SBRT in patients with omCRPC may delay initiation of next line systemic therapy in well selected patients, including those with ≥1 untreated non-progressing metastases. [Table: see text]

Ulcerating skin lesions from blastic plasmacytoid dendritic cell neoplasm responding to low-dose radiotherapy-acase report and literature review.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is arare hematologic malignancy that can manifest with skin nodules and erythematous plaques. In most cases BPDCN progresses rapidly, causing multiple skin lesions and also affecting internal organs and bone marrow, warranting initiation of systemic therapies or hematopoietic stem cell transplantation (HCT). Although not curative, radiotherapy for isolated lesions might be indicated in case of (imminent) ulceration and large or symptomatic lesions. To this end, doses of 27.0-51.0 Gy have been reported. Here, we present the case of an 80-year-old male with BPDCN with multiple large, nodular, and ulcerating lesions of the thorax, abdomen, and face. Low-dose radiotherapy of 2 × 4.0 Gy was administered to several lesions, which resolved completely within 1week with only light residual hyperpigmentation of the skin in affected areas and reliably prevented further ulceration. Radiotoxicity was not reported. Therefore, low-dose radiotherapy can be an effective and low-key treatment in selected cases of BPDCN, especially in apalliative setting, with afavorable toxicity profile.

Is Food-Triggered Atopic Dermatitis a Form of Systemic Contact Dermatitis?

Food allergy in atopic dermatitis is mediated by complex immune interactions between genetics, diet, environment, and the microbiome. When contact between inflamed skin and food antigens occurs, contact hypersensitivity can develop. Consequently, systemic contact dermatitis (SCD) can occur after ingestion of allergenic foods or food additives in the setting of a Th2 response with CLA-positive T cells, triggering dermatitis where skin resident memory lymphocytes reside. This phenomenon explains food-triggered dermatitis. Atopy patch tests (APTs) detect sensitization to food proteins responsible for SCD, which in turn can be confirmed by oral food challenge with delayed interpretation. We summarize the literature on using APTs to identify foods for oral challenge with dermatitis as an outcome. In dermatitis patients at risk for Th2 skewing based on a history of childhood-onset flexural dermatitis, shared decision-making should include a discussion of identifying and avoiding food and food additive triggers, as well as identifying and avoiding all contact allergens, prior to initiation of systemic therapy for dermatitis.

Spatial Tumor Heterogeneity in a Young Female with Lung Adenocarcinoma and Brain Metastasis

Small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) are the two different forms of lung cancer, the latter subtype accounts for approximately 85% of cases. Lung cancer is estimated to be the main cause of all cancer deaths, accounting for nearly 1,800,000 deaths globally in 2020. In this clinical case, we describe a female patient with non-specific symptoms over an approximate duration of one and a half years. Metastatic lung adenocarcinoma was diagnosed after the onset of severe neurological symptoms, brain surgery, and historical analysis of the large pathological brain mass. Following this, the tumor in the lung, which was small in size and the sole metabolically active site of the disease, was surgically removed. The recurrence in the brain and the onset of new neurological symptoms occurred rapidly—within three months, necessitating a second operation. Histological examination of the primary tumor and metastasis unveiled significant disparities–the primary tumor was moderately differentiated with PD-L1 expression (programmed death-ligand 1) within the range of 1 to 49%, while metastasis was poorly differentiated and PD-L1 negative, both absent of EGFR mutations (epidermal growth factor receptor) and ALK fusion (anaplastic lymphoma kinase). Following two brain operations, the patient underwent three-dimensional conformal radiation therapy (3DCRT). Subsequently, the initiation of systemic therapy was postponed by a two-month interval due to the activation of chronic hepatitis C virus infection. This case study contributes to the growing body of knowledge aimed at enhancing our grasp of tumor heterogeneity and dynamics of progression.